PET imaging of metabotropic glutamate receptor subtype 5 (mGluR5) in smokers
Funda AkkusSimon M. AmetameyCyrill BurgerValérie TreyerAnass JohayemYves P. AubersonJudit SóvágóBaltazar Gomez‐MancillaAlfred BuckGregor Hasler
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334 Objectives The metabotropic glutamate receptor 5 (mGluR5) has been implicated in addiction. Specifically, the mGluR5 has been suggested to be particularly involved in nicotine addiction. In order to verify whether smoking was associated with changes in the availability of mGluR5, we performed PET studies with 11C-ABP688 in smokers and non-smokers. Methods Fourteen smokers (8 women, mean age 33.5 years; 6 men, mean age 37.8 years; average nicotine consumption: 17 cigarettes per day) and fourteen healthy controls (8 women, mean age 34.6 years; 6 men, mean age 39 years) were recruited for the study. Clinical measures included nicotine addiction as assessed by the Fragestrom Test for Nicotine Dependence (FTND). PET images of mGluR5 distribution were acquired after a bolus injection of 780-800 MBq of 11C-ABP688. Total volume of distribution normalized to the cerebellum was used as a measure of receptor density. Differences between smokers and non-smokers in the binding of 11C-ABP688 were assessed in pre-defined regions-of-interest. Results A marked global reduction of 22.8±4.3% in mGluR5 density in smokers relative to non-smokers was found. The most prominent reductions were found in the left orbitofrontal cortex (33.7%, p Conclusions These results suggest an important role of mGluR5 in the pathophysiology of nicotine dependence in humans. The reductions in mGluR5 may represent compensatory and/or pathogenetic changes associated with nicotine addictionKeywords:
Orbitofrontal cortex
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Metabotropic glutamate receptors 2/3 (mGluR2/3) and 5 (mGluR5) are novel therapeutic targets for major depression (MD), bipolar disorder (BD) and schizophrenia. We aimed to determine whether mGluR2/3 and mGluR5 binding in the anterior cingulate cortex (ACC), a brain region essential for the regulation of mood, cognition and emotion, were differentially altered in these pathologies.Using postmortem human brains derived from 2 cohorts, [(3)H]LY341495 binding to mGluR2/3 and [(3)H]MPEP binding to mGluR5 were measured by receptor autoradiography in the ACC. The first cohort comprised samples from individuals who had MD with psychosis (MDP), MD without psychosis (MDNP) and matched controls (n = 11-12 per group). The second cohort comprised samples from individuals who had MDNP, BD, schizophrenia and matched controls (n = 15 per group).No differences in mGluR2/3 or mGluR5 binding were observed in the MDP, MDNP, BD or schizophrenia groups compared with the control group (all p > 0.05). Importantly, there were also no differences in binding densities between the psychiatric disorders (p > 0.05). We did, however, observe age-related effects, with consistent negative associations between mGluR2/3 and age in the control group (r < -0.575, p < 0.025) and the psychotic disorder groups (MDP and schizophrenia: r = -0.765 to -0.515, p < 0.05), but not in the mood disorder groups (MDNP, BD).Replication in larger independent cohorts and medication-naive individuals would strengthen these findings.Our findings suggest that mGluRs are unaltered in the ACC; however, the presence of altered receptor function cannot be discounted and requires further investigation. Taken together with previous studies, which report differential changes in mGluR2, 3 and 5 across these disorders, we suggest mGluRs may be affected in a brain region-specific manner.
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In previous research, nicotine-dependent men exhibited lower putamen D2/D3 dopamine-receptor availability than non-smokers (Fehr et al.2008), but parallel assessments were not performed in women. Women and men (19 light smokers, 18 non-smokers) were tested for differences due to sex and smoking in striatal D2/D3 dopamine-receptor availability, using positron emission tomography with [18F]fallypride. Receptor availability was determined using a reference region method, in striatal volumes and in whole-brain, voxel-wise analysis. Significant sex×smoking interactions were observed in the caudate nuclei and putamen. Post-hoc t tests showed that male smokers had significantly lower D2/D3 dopamine-receptor availability than female smokers (−17% caudate, −21% putamen) and male non-smokers (−15% caudate, −16% putamen). Female smokers did not differ from non-smokers. Whole-brain analysis demonstrated no statistically significant voxels or clusters. These results suggest that low receptor availability may confer vulnerability to nicotine dependence or that smoking selectively affects D2/D3 receptor down-regulation in men but not women.
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The purpose of this study was to assess, in a large sample of healthy young adults, sex differences in the binding potential of [11C]ABP688, a positron emission tomography (PET) tracer selective for the metabotropic glutamate type 5 (mGlu5) receptor.High resolution [11C]ABP688 PET scans were acquired in 74 healthy volunteers (25 male, 49 female, mean age 20 ± 3.0). Mean binding potential (BPND = fND * (Bavail / KD)) values were calculated in the prefrontal cortex, striatum, and limbic regions using the simplified reference tissue model with cerebellar grey matter as the reference region.[11C]ABP688 BPND was significantly higher in men compared to women in the prefrontal cortex (p < 0.01), striatum (p < 0.001), and hippocampus (p < 0.05). Whole-brain BPND was 17% higher in men. BPND was not related to menstrual phase in women.Binding availability of mGlu5 receptors as measured by PET [11C]ABP688 is higher in healthy men than women. This likely represents a source of variability in [11C]ABP688 studies and could have relevance for sex differences in cognitive-behavioral functions and neuropsychiatric disorders.
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Nicotine addiction is a major public health problem, resulting in primary glutamatergic dysfunction. We measured the glutamate receptor binding in the human brain and provided direct evidence for the abnormal glutamate system in smokers. Because antagonism of the metabotropic glutamate receptor 5 (mGluR5) reduced nicotine self-administration in rats and mice, mGluR5 is suggested to be involved in nicotine addiction. mGluR5 receptor binding specifically to an allosteric site was observed by using positron emission tomography with [(11)C]ABP688. We found a marked global reduction (20.6%; P < 0.0001) in the mGluR5 distribution volume ratio (DVR) in the gray matter of 14 smokers. The most prominent reductions were found in the bilateral medial orbitofrontal cortex. Compared with 14 nonsmokers, 14 ex-smokers had global reductions in the average gray matter mGluR5 DVR (11.5%; P < 0.005), and there was a significant difference in average gray matter mGluR5 DVR between smokers and ex-smokers (9.2%; P < 0.01). Clinical variables reflecting current nicotine consumption, dependence and abstinence were not correlated with mGluR5 DVR. This decrease in mGluR5 receptor binding may be an adaptation to chronic increases in glutamate induced by chronic nicotine administration, and the decreased down-regulation seen in the ex-smokers could be due to incomplete recovery of the receptors, especially because the ex-smokers were abstinent for only 25 wk on average. These results encourage the development and testing of drugs against addiction that directly target the glutamatergic system.
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Abstract Introduction Metabotropic glutamate receptors play a critical role in the pathogenesis of Alzheimer's disease due to their involvement in processes of memory formation, neuroplasticity, and synaptotoxity. The objective of the current study was to study mGluR5 availability measured by [ 11 C]‐ABP688 (ABP) in patients with clinically diagnosed Alzheimer's dementia (AD). Methods A bolus‐infusion protocol of [ 11 C]‐ABP688 was applied in 9 subjects with AD and 10 cognitively healthy controls (Controls) to derive distribution volume estimates of mGluR5. Furthermore, we also estimated cerebral perfusion by averaging early frame signal of initial ABP bolus injection. Results Subjects with Alzheimer's dementia (mean age: 77.3/ SD 5.7) were older than controls (mean age: 68.5/ SD : 9.6) and scored lower on the MMSE (22.1/SD2.7 vs. 29.0/SD0.8). There were no overall differences in ABP signal. However, distribution volume ratio (DVR) for ABP was reduced in the bilateral hippocampus (AD: 1.34/ SD : 0.40 vs. Control: 1.84/ SD :0.31, p = .007) and the bilateral amygdala (AD:1.86/ SD :0.26 vs. Control:2.33/ SD :0.37 p = .006) in AD patients compared to controls. Estimate of cerebral blood flow was reduced in the bilateral hippocampus in AD (AD:0.75/ SD :0.10 vs. Control:0.86/ SD :0.09 p = .02). Conclusion Our findings demonstrate reduced mGluR5 binding in the hippocampus and amygdala in Alzheimer's dementia. Whether this is due to synaptic loss and/or consecutive reduction of potential binding sites or reflects disease inherent mechanisms remains to be elucidated in future studies.
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